Project Marilyn RFC

My story
From when I was young, I spent a lot of time programming computers. In high school, my science fair project was a hand coded n-body gravitational simulator, and many of my close friends went into the computer industry. Ultimately after some interventions by my friend (and now board member) Stephen Ridley, and through benefitting from code that other programmers had shared with me, I began to understand the value of the open-source philosophy. I also began to comprehend how proprietary products can be problematic: an understanding that is deepening as I get older and more experienced.

Yet when I began my graduate career in chemistry and biology, what I found was an industry that still clung to closed, proprietary economic models, and had very little hope of grasping the philosophy behind the open-source revolution that transformed the way we use software. While our counterparts in high-technology are closing legal doors behind patent trolls and exploring the space of open culture from evolving an ecosystem open licences to testing out the concept of open corporations, biologists and chemists still play games with patent language, and silo themselves in secret compartments to keep out knowledge leaks. To be sure, there are some initiatives trying to break down these barriers, such as the biobricks foundation and openwetware, but – resistance is still the dominant reaction.

As younger scientists and more computer-savvy scientists emerge into the higher levels of academia and industry, the seeds for change will be planted, but that will not be enough; the status quo can always argue that ‘this is the way things are done; no other way will work’, regardless of if it’s actually been tried. Much like how Linux (and later, the LAMP stack) was a decisive factor in producing the sea change of opinion, what biologists and chemists need is a ‘proof of principle’ that demonstrates that modern drug development can be done differently. Thanks to my skill at ‘having been at the right place at the right time’, I believe that I have an outside chance of making this demonstration. To accomplish this, I’ve founded a non-profit organization dedicated to open science, indysci dot org, and using this platform I intend to push forward several examples of biological and chemical innovations that ‘leverage the insights gained by the open-source movement’.

We’re getting ready to launch our first initiative – Project Marilyn. This is a crowdfunded effort to develop a IP-free pharmaceutical. Why crowdfunded? Because we’d like to prove that there is a broad social desire to see this happen. Following the concept of Linus’ law, we’d like for many eyes to check our work and make sure what we are doing is okay before we ask for your money. So I present to you the Project Marilyn RFC. The RFC will get more detailed than the broad-picture story I just told you; and the detail-oriented can drill down deeper to examine our plans more carefully. Especially important is if you can forward it to people who you think will find this to be interesting – supporters and skeptics alike.

RFC
The purpose of this RFC is to solicit public involvement in the crafting of Project Marilyn (PM). After a final round of editing by the project lead, the RFC (minus this section) will be presented to the indysci dot org board for approval as the offical PM proposal. Questions about PM are encouraged, we will be putting together a FAQ that addresses issues and concerns that may arise, some of which we may not have anticipated yet. This page contains the most recent version of the RFC. To track the evolution of this RFC, please see the github repo.

Summary
Project Marilyn is a nonprofit venture to raise money using the crowdfunding mechanism to bring several anticancer drug candidates through preclinical trials. Unlike most pharmaceutical research, the candidates brought forward by PM will not be patented and instead released to the public domain, so that ultimately manufacturers can produce these candidates inexpensively without licencing costs. The project lead, Isaac Yonemoto, was involved in producing and conducting initial tests on the parent compound, 9-deoxysibiromycin (9DS).

Background
Sibiromycin was discovered in the last century by researchers in Siberia. It is a toxic compound produced by soil bacteria and functions by arresting DNA replication. Therefore, it has potential as an anticancer chemotherapeutic. Early research on sibiromycin was abandoned when it was discovered to also be cardiotoxic. Later research on the family of chemicals identified a single oxygen atom that is likely to be the cause of the undesirable cardiotoxicity. Dr. Barbara Gerratana devised a method to produce analogs of sibiromycin lacking this oxygen atom, hence 9-deoxysibiromycin. Initial tests indicate that as designed, 9DS is less cardiotoxic than the parent sibiromycin, and surprisingly, more potent against cancer cell lines in vitro. Recently, a related compound, SJG-136, has met some success in initial clinical trials.

Dr. Gerratana departed from her position as a primary investigator, and once again research on the sibiromycin family was abandoned. Project Marilyn picks up where this left off, taking advantage of the expiration of the patentability of 9DS and continuing with the intent of producing more analogs and releasing these to the public domain as well. An open-access version of the publication reporting 9DS is available.

What remains to be done is to bring 9DS through further preclinical experimentation, including animal studies. A pharmacokinetics study and a xenograft study will evaluate suggested dosage and measure efficacy against select cancer lines in vivo. Pharmaceutical development is often ‘a numbers game’; to further improve the likelihood of success, PM seeks to produce analogs of 9DS for preclinical evaluation, so that ultimately ‘best candidates’ can be put forth for clinical trials. The method developed by Dr. Gerratana is particularly amenable to the production of analogs.

Project Lead Qualifications
Isaac Yonemoto earned his PhD in chemistry from The Scripps Research Institute, for research on protein folding dynamics. Subsequently, he performed postdoctoral research under the supervision of Barbara Gerratana, gaining firsthand experience in the production, analytical verification, and handling of sibiromycin and analogs. After this, he performed postdoctoral research at the J. Craig Venter Institute, gaining experience in synthetic biology techniques. A full CV is available here.

Full Scientific Description
A full scientific description is available for examination here.

Fundraising
Fundraising will begin on January 7th, 2014 and last till February 7th, 2014, not inclusive of extensions. To improve the likelihood of success (including a small budgetary margin), the fundraising minimum “tilt value” will be 750,000 USD. A first stretch goal will be announced and described at 1,000,000 USD and will tilt at 1,250,000 USD. A second stretch goal will be announced and described at 1,500,000 USD and will tilt at 1,750,000 USD. If enough funds are collected to reveal a stretch goal (i.e. at the 1,000,000 and 1,500,000 levels), then the fundraising period will be extended one week (i.e. to February 14th, and February 21st, respectively). Although we will not ‘reveal’ the stretch goals at the moment, both stretch goals will be projects dedicated to the treatment of cancer, and will be well-posed to share laboratory infrastructure with the primary PM objective. All pharmaceutical candidates developed for the primary or stretch goals will not be patented and will be released to the public domain.

Success Criteria
PM will be considered to have succeded if three sibiromycin derivatives (including 9DS) have completed a suite of preclinical trials, to include NCI-60 screen, pharmacokinetic studies and xenograft studies.

Secondary Objectives
PM will also pursue some secondary objectives which will not affect the determination of success but may in the short term ease the production of sibiromycin analogs for preclinical testing and in the long term improve the likelihood of regulatory approval or commercial viability. These include, but are not limited to: development of producer strains, improvement of growth and harvesting conditions for producer strains, and improvement of purification process.

Scientific Advisor
PM has not at the moment designated scientific advisor(s), we are soliciting recommendations for researchers with two years of experience willing to give ~10h a year to provide independent oversight for the project. The advisor will be responsible for issuing an interim go/no go decision, and be responsible for determining if the project was successful at its conclusion. Compensation may be available. Especially welcome are scientists interested in supporting public domain pharmaceuticals, scientists with drug development experience, or scientists with clinical research experience in the field of oncology.

Timeline
Detailed PM timeline is available as a separate document here.

Budget
Detailed PM budgets are available as a separate document hereSummary: Budgets for 750,000 USD, 1,250,000 USD, and 1,750,000 USD are presented. Note that higher fundraising will result in increased budgetary margins. Also note that the 1,750,000 USD stretch goals involves experimentation over a longer timeframe than the other two fundraising outcomes. Employees will not be penalized if the project concludes earlier as a result of achieving the project objectives.

Surplus Budget
Upon conclusion of the project, the use of the surplus budget will depend on the total amount of funds raised by crowdfunding:

750,000~1,000,000 USD, the surplus budget will be transferred to a 501(c)(3) nonprofit cancer research hospital, such as City of Hope hospital.

1,000,000~1,250,000 USD, no more than half of the surplus budget will be used to pilot the first stretch goal with the intent to generate data to re-pitch the first stretch goal pending the success of PM primary objective. The remainder will be transferred to a 501(c)(3) nonprofit cancer research hospital.

1,250,000~1,500,000 USD, the surplus budget will be transferred to a 501(c)(3) nonprofit cancer research hospital.

> 1,500,000 USD no more than half of the surplus budget will be used to pilot or continue the first and second stretch goals. The remainder will be transferred to a 501(c)(3) nonprofit cancer research hospital.

10% time
Acknowledging that freedom to pursue tangential or unrelated science can yield important insights for the main project, postdoctoral researchers (but not technicians, without approval of the project lead) will be encouraged to pursue “10% time” projects which may or may not be related to PM, if funds are available. Funds for reagents, equipment, and supplies for 10% time will derive from the indysci general budget, and not the PM budget, unless a compelling connection to PM can be argued. The project lead will be responsible for making this determination. Salaries for 10% time will not be prorated.

Other Projects
The project lead will reserve the right to pursue at most one other primary scientific project outside of the scope of PM and the PM stretch goals. If such a project is funded, then the lead salary will be prorated to 50%.